Meiosis is a specialized cell division process that results in the formation of haploid gametes (i.e.: eggs and sperm) and is therefore essential for sexual reproduction and generating genetic diversity. The reduction of the chromosome complement by half is accomplished by following a single round of DNA replication with two consecutive rounds of chromosome segregation (meiosis I and meiosis II). Achieving accurate chromosome segregation is paramount for the successful formation of haploid gametes. To segregate properly, chromosomes must undergo a series of steps that are unique to meiosis I, including: (1) homologous pairing, (2) formation of a "zipper-like" structure (the synaptonemal complex or SC) between aligned homologs, and (3) completion of meiotic recombination leading to physical attachments (chiasmata) between homologs. Significantly, errors in any of these steps lead to chromosome nondisjunction, with disastrous consequences including miscarriages and birth defects such as Down syndrome. Our goal is to investigate the roles, macromolecular assembly and regulation of the SC, whose functions are poorly understood and a matter of much debate despite its ubiquitous presence from yeast to humans. Focusing on this goal will reveal how synapsis intersects with the regulation of meiotic progression and promotes accurate chromosome segregation. We are addressing this important issue by studying it in the nematode C. elegans, an ideal model system for meiotic studies, amenable to various genetic, molecular, biochemical and cytological approaches. We have recently identified four critical SC components (SYP-1, SYP-2, SYP-3 and SYP-4), proteins that regulate SC assembly (CRA-1), meiotic recombination (HIM-18), and SC disassembly and sister chromatid cohesion during meiosis I (LAB-1). Beginning with the analysis of the molecular mechanisms through which several of these proteins function during meiosis, we propose to address the fundamental issues of how pairing, synapsis and recombination intersect and are regulated resulting in accurate chromosome segregation. We will do this by combining cytological observations done in the context of an intact 3-D nuclear architecture in this system, with results from molecular, genetic and biochemical approaches. Taken together, this application will provide significant new insights into the molecular mechanisms underlying accurate meiotic chromosome segregation and move us forward in our understanding of analogous processes in higher eukaryotes.

Public Health Relevance

Meiosis is a specialized cell division program required for the production of eggs and sperm and therefore essential for human reproduction. Errors during meiosis are predicted to account for approximately 35% of all miscarriages in humans and birth defects such as Down syndrome. The proposed research will investigate the molecular mechanisms promoting accurate meiotic chromosome segregation thereby laying the foundation for the development of effective preventive strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072551-08
Application #
8305590
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Janes, Daniel E
Project Start
2005-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
8
Fiscal Year
2012
Total Cost
$339,806
Indirect Cost
$139,331
Name
Harvard University
Department
Genetics
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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